Immediate vs delayed ADT in recurrent prostate cancer: a review

In March this year we reported briefly on an article by Van Poppel et al. reviewing available data on the adjuvant and the delayed use of hormone therapy in the treatment of prostate cancer and the related issue of PSA recurrence (particularly in high risk patients).

We should be clear that we do not believe this article adds to the current literature on this topic. It is “only” a review, but it appears to be a good review and some readers have brought this article to our attention and implied that we should comment further, particularly since the appearance of a “Beyond the Abstract” update the other day on the UroToday website.

It is common for patients with biochemical recurrence (i.e., a rising PSA) after first-line radiation or surgery to be treated with androgen deprivation therapy (ADT) before there is any actual evidence of metastatic disease. However, the clinical benefit of this approach is uncertain. There have been no randomized trials of ADT as treatment for patients with a rising PSA after clear evidence of biochemical failure of first-line therapy. There is no conclusive evidence that hormone therapy (HT) after radical prostatectomy or other forms of first-line therapy will either prolong survival or reduce morbidity. And there is no absolute consensus on how patients with PSA recurrence after first-line therapy should be treated. It shoulod, however, be made clear that in the case of patients who have received first-line surgery, and have a rising PSA with a relatively low doubling time, there appears to be a growing agreement that radiation therapy without the addition of hormone therapy may be the most appropriate treatment, but even this is not accepted universally.

As Van Poppel and his colleagues point out,  the effect of immediate adjuvant ADT after first-line therapy has been studied prospectively (by Messing et al., by Wirth et al., and by McLeod et al.). These groups of authors carried out randomized clinical trials of various forms of hormone therapy as immediate follow-up treatment after first-line therapy in patients at relatively high risk for disease progression. However, only one of these trials (first reported by Messing et al. in 1999) has demonstrated a survival benefit from immediate ADT — in patients who had positive lymph nodes at the time of surgical treatment. The studies by Wirth et al. (of flutamide monotherapy) and by McLeod et al. (of bicalutamide monotherapy) showed no benefit to hormone therapy.

It is true that several different retrospective analyses have been carried out on the use of immediate and delayed hormone therapy in patients with surgically managed, lymph node-positive prostate cancer. However, these studies have not made it possible to develop definitive recommendations about the timing and duration of adjuvant hormone therapy after radical prostatectomy. Indeed the degree to which these data are relevant to men with rising PSA levels post-surgery is utterly unclear.

We do have available data from three retrospective studies of patients with post-surgical PSA recurrence who were treated with hormone therapy. Moul et al. have shown that early ADT after PSA recurrence has no impact on clinically evident, metastasis-free survival but can delay the onset of metastases in high-risk patients with Gleason score > 7 and/or  a PSA doubling time of ≤ 12 months. Siddiqui et al. demonstrated that adjuvant, post-surgical ADT (within 90 days of surgery) can induce some degree of cancer-specific survival and systemic progression-free survival in a large cohort of high-risk patients (but that the survival benefit is lost when ADT is delivered at the time of PSA recurrence or systemic progression). Finally, Makarov et al.‘s data suggest that ADT therapy delayed until there is clear evidence of metastasis after radical prostatectomy leads to extended  survival, with a median time from surgery to death of 14 years.

Now in assessing the potential pros and cons of early vs. delayed ADT, we certainly need to appreciate the fact that ADT exposes many patients with prostate cancer to the well-known and significant side effects of that therapy. Given this fact, if there is limited potential for a survival benefit, it is very reasonable to ask whether the adverse effects of long-term hormone therapy are worth that limited survival opportunity.

Currently, there are ongoing trials of a wide range of non-traditional forms of hormone therapy in the adjuvant and the biochemical recurrence setting,  using intermittent androgen deprivation, non-steroidal anti-androgens, and a combination of finasteride and a non-steroidal anti-androgen. However, Von Poppel and his co-authors suggest that until a randomized trial of immediate vs delayed LHRH agonist therapy is conducted, in men with a rising PSA after first-line therapy, we will not have primary evidence to support or discourage this type of widespread treatment of men with biochemical recurrence after surgery or after other forms of first-line therapy.

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